Influenza A is a classic emerging disease. Genetic reassortment and/or adaptation to a new host can cause disastrous pandemics with high mortality. Influenza virus infects and replicates in the respiratory epithelium and induces inflammatory infiltrates comprised of neutrophils and monocytes. The primary innate immune response is initiated at the apical surface of the airway epithelium, at a location where a recently identified NADPH oxidase, Duox, resides. Duox generates reactive oxygen species, and has been implicated in wound healing and in changes of the pH and redox environment. These features position Duox as an ideal participant in the local immune response during airborne microbial pathogenesis. This project uses forward genetics to elucidate how Duox proteins regulate intracellular signaling pathways essential for anti-viral host defense. Duox and the phagocyte oxidase Nox2 are also prime candidates for regulating leukocyte trafficking into the lungs. An in vitro differentiated human lung epithelium and isolated human neutrophils will be combined in a model system that permits genetic manipulation and visualization of structural changes by immunofluorescence and electron microscopy. Our studies will show if oxidases are a promising target for therapeutic drug development. [unreadable] [unreadable] [unreadable] [unreadable]